title: Liver receptor homolog-1 is critical for adequate up-regulation of Cyp7a1 gene transcription and bile salt synthesis during bile salt sequestration.
abstract: Liver receptor homolog-1 (LRH-1) is a nuclear receptor that controls a variety of metabolic pathways. In cultured cells, LRH-1 induces the expression of CYP7A1 and CYP8B1, key enzymes in bile salt synthesis. However, hepatic Cyp7a1 mRNA levels were not reduced upon hepatocyte-specific Lrh-1 deletion in mice. The reason for this apparent paradox has remained elusive. We describe a novel conditional whole-body Lrh-1 knockdown (LRH-1-KD) mouse model to evaluate the dependency of bile salt synthesis and composition on LRH-1. Surprisingly, Cyp7a1 expression was increased rather than decreased under chow-fed conditions in LRH-1-KD mice. This coincided with a significant reduction in expression of intestinal Fgf15, a suppressor of Cyp7a1 expression, and a 58% increase in bile salt synthesis. However, when fecal bile salt loss was stimulated by feeding the bile salt sequestrant colesevelam, Cyp7a1 expression was up-regulated in wildtype mice but not in LRH-1-KD mice (+593% in wildtype versus +9% in LRH-1-KD). This translated into an increase in bile salt synthesis of +272% in wildtype versus +21% in LRH-1-KD mice.
  
  
  CONCLUSIONS
  Our data provide mechanistic insight into a missing link in the maintenance of bile salt homeostasis during enhanced fecal loss and support the view that LRH-1 controls Cyp7a1 expression from two distinct sites, i.e., liver and ileum, in the enterohepatic circulation.
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. c.out@med.umcg.nl
authors.forename: Carolien
authors.initials: C
authors.lastname: Out
authors.forename: Jurre
authors.initials: J
authors.lastname: Hageman
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Han
authors.initials: H
authors.lastname: Gerrits
authors.forename: Maarten D
authors.initials: MD
authors.lastname: Sollewijn Gelpke
authors.forename: Trijnie
authors.initials: T
authors.lastname: Bos
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D000069472:Colesevelam Hydrochloride; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000502:physiology; D007082:Ileum / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D000499:Allylamine; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D000069472:Colesevelam Hydrochloride